4 March 2002 16:43 EST

by Apoorva Mandavilli, BioMedNet News

[caption and credit]

Trials to test a chimeric vaccine against the West Nile virus in monkeys will begin next month, researchers at the US National Institute of Allergy and Infectious Diseases (NAIAD) revealed today. But response to the announcement from others in the field ranges from rave reviews to outright skepticism.

Alexander Pletnev and his colleagues at NIAID have created a chimeric virus with the backbone of the dengue virus type 4 and the structural premembrane and envelope membrane proteins of the West Nile virus (WNV) strain NY99.

When they injected suckling mice intracerebrally with the vaccine, the chimeric virus was at least 28,000 times less virulent than the parent West Nile virus - "very, very promising results," said Pletnev. The vaccine completely protected immunized mice from WNV infection.

If all goes well, trials in monkeys will progress over the next few months, and human trials may begin next year, he says. But that may depend entirely on whether he can find access to a level III facility, required for work with WNV. "It's a terrible project because most of my time was [spent] waiting for facilities to do the experiment," he said. "It's not easy - so many restrictions, so many regulations."

Pletnev is also creating chimeric viruses for vaccines against the powassan virus and St. Louis encephalitis.

"The results are fairly surprising, overall," said Thomas J. Chambers, associate professor of molecular microbiology and immunology at St. Louis University. When you combine two viruses, Thomas explained, "you never really know what you're going to come up with." But because the vaccine was introduced directly into the central nervous system of newborn mice, he said, "I would have predicted more virulence than what they observed."

That a chimeric virus of such low virulence was still able to confer full immunity, "that's almost unprecedented," he added.

West Nile virus is one of more than 60 flaviviruses, a group that includes St. Louis encephalitis, Japanese encephalitis, yellow fever virus, dengue and many other important human pathogens. A zoonotic disease of increasing threat, WNV is a particular danger to horses and certain species of birds. Although humans are an incident host, the virus can also cause encephalitis in people with a weakened immune system. It affected nearly 70 people in 1999.

Pletnev first developed the method in 1991 to produce a chimera with dengue and tick-borne encephalitis virus, a class IV virus that causes severe infection with 80% mortality. Human trials for that vaccine are due to begin later this year.

Scientists at the Centers for Disease Control and Prevention (CDC) and the Boston-based Acambis, Inc. are now using similar methods for their own experiments. A chimeric virus with the West Nile and yellowfever vaccines at Acambis, Inc. is much further along than the NIAID vaccine, which was published today in the Proceedings of the National Academy of Sciences, says CDC research microbiologist Jeffrey Chang. He declined to elaborate.

"The basic problem with chimeric viruses is a tremendous safety concern," said Chang, who developed an equine WNV vaccine now in trials. That is a DNA vaccine, in which WNV genes expressed in a plasmid stimulate an immune response.

"There are safety concerns with any attenuated or recombinant viruses," he said. They can revert back to wild type, Chang points out, and the different host ranges in the chimera could lead to replication of one virus in a host for the other. The chimera may also recombine with wild-type virus, he points out, noting that the polio vaccine recombined with wild-type enterovirus last year in Jamaica.

"In principle, I agree with that comment," said Chambers, but DNA vaccines like Chang's equine vaccine also have safety issues, he adds.

Picture caption and credit:
Photomicrograph of brain tissue from a West Nile encephalitis patient, showing antigen-positive neurons and neuronal processes (in red), CDC/W.-J. Shieh and S. Zaki.

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